NOVEL FORMULATIONS OF PROTON PUMP INHIBITORS AND METHODS OF USING THESE FORMULATIONS
The present invention relates to combinations of a proton pump inhibiting agent and at least one buffering agent that have been found to possess improved bioavailability, chemical stability, physical stability, dissolution profiles, disintegration times, as well as other improved pharmacokinetic, pharmacodynamic, chemical and/or physical properties. The present invention is directed to methods, kits, combinations, and compositions for treating, preventing or reducing the risk of developing a gastrointestinal disorder or disease including nocturnal acid breakthrough, or the symptoms associated therewith
1 . A pharmaceutical composition in a tablet dosage form comprising:
(a) about 10 mgs to about 100 mgs of at least one acid labile bicyclic-aryl-imidazole proton pump inhibiting agent;
(b) at least one antacid in an amount sufficient to increase gastric fluid pH to a pH that prevents acid degradation of at least some of the proton pump inhibitor in the gastric fluid; wherein the antacid comprises at least about 400 mgs of NaHCO 3 ; and
(c) about 0.5 wt-% to about 3 wt-% of a hydrophilic lubricant;
wherein the composition achieves an in vitro initial rise in pH within about 4 minutes.
2 . The pharmaceutical composition of claim 1 , wherein the composition achieves an in vitro initial pH of at least about 4 within about 2 minutes.
3 . The pharmaceutical composition of claim 1 , wherein the hydrophilic lubricant is sodium stearyl fumarate.
4 . The pharmaceutical formulation according to claim 1 , wherein the proton pump inhibitor is omeprazole, esomeprazole or lansoprazole, or a pharmaceutically acceptable salt thereof.
5 . The pharmaceutical formulation according to claim 1 , wherein the solid dosage form further comprising an antacid selected from potassium bicarbonate, sodium carbonate, calcium carbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, and mixtures thereof; and the total amount of antacid present in the capsule is about 10 mEq to about 30 mEq.
6 . The pharmaceutical formulation according to claim 1 , wherein the sodium bicarbonate is present in an amount of at least about 800 mgs.
7 . The pharmaceutical formulation according to claim 1 , wherein the composition further comprises between about 2 wt-% to about 6 wt-% croscarmellose sodium.
8 . A method of treating a gastrointestinal disorder in a patient comprising the step of administering a composition in a tablet dosage form comprising:
(a) about 10 mgs to about 100 mgs of at least one acid labile bicyclic-aryl-imidazole proton pump inhibiting agent;
(b) at least one antacid in an amount sufficient to increase gastric fluid pH to a pH that prevents acid degradation of at least some of the proton pump inhibitor in the gastric fluid; wherein the antacid comprises at least about 400 mgs of NaHCO 3 ; and
(c) about 0.5 wt-% to about 3 wt-% of sodium stearyl fumarate;
wherein the composition is administered to a fasted subject daily and the T max of the proton pump inhibitor is less than about 45 minutes on Day 1 and Day 7 of administration of the composition.
9 . The pharmaceutical formulation according to claim 8 , wherein the initial serum concentration of the proton pump inhibitor is greater than about 0.3 μ/ml within about 45 minutes after oral administration of the tablet to the subject.
10 . The pharmaceutical formulation according to claim 9 , wherein the average C max of the proton pump inhibiting agent is less than about 1250 ng/ml after oral administration of the tablet to the subject.
11 - 26 . (canceled)
27 . A pharmaceutical composition in a tablet dosage form comprising:
(a) about 20 to about 100 mg of a proton pump inhibitor; and
(b) at least about 400 mgs of directly compressible sodium bicarbonate;
wherein the hardness of the tablet is between 10-20 kP.
28 . The pharmaceutical composition of claim 27 , wherein the tablet achieves a hardness of 10-20 kP with less than 10,000 lbs of force.
29 . The pharmaceutical composition of claim 28 , wherein the tablet achieves an in vitro initial rise in pH within about 4 minutes.
30 . The pharmaceutical composition of claim 27 , wherein upon administration to a fasted subject, the tablet provides a T max between about 30 minutes and about 45 minutes on Day 1.
31 . The pharmaceutical composition of claim 27 , wherein upon administration to a fasted subject, the tablet provides a T max of less than about 45 minutes on Day 7.
32 . The pharmaceutical composition of claim 27 , wherein the tablet comprises 750 mgs of the compressible sodium bicarbonate.
33 . The pharmaceutical composition of claim 27 , wherein the directly compressible sodium bicarbonate comprises between about 90-98 wt-% sodium bicarbonate and about 2-10 wt-% hydroxypropyl cellulose.
34 . The pharmaceutical composition of claim 27 , wherein the directly compressible sodium bicarbonate comprises about 2 wt-% to about 10 wt-% hydroxypropyl cellulose.
35 . The pharmaceutical composition of claim 27 , wherein the directly compressible sodium bicarbonate is about 97 wt-% sodium bicarbonate and about 3 wt-% hydroxypropyl cellulose.
36 . The pharmaceutical composition of claim 27 , wherein the directly compressible sodium bicarbonate is about 95 wt-% sodium bicarbonate and about 5 wt-% hydroxypropyl cellulose.
37 . The pharmaceutical composition of claim 27 , wherein the directly compressible sodium bicarbonate comprises about 5 wt-% to about 10 wt-% pregelatinized starch.
38 . The pharmaceutical composition of claim 27 , wherein the binder is hydroxypropyl cellulose and is present in an amount of about 3 wt-%.
39 . The pharmaceutical composition of claim 38 , wherein the disintegrant is croscarmellose sodium and is present in an amount of about 3 wt-%.
40 . The pharmaceutical composition of claim 27 , wherein the lubricant is sodium stearyl fumarate and is present in an amount of about 0.5 wt-% to about 5 wt-%.
41 . The pharmaceutical composition of claim 27 , wherein the directly compressible sodium bicarbonate is a combination of sodium bicarbonate and hydroxypropyl cellulose.
42 . A pharmaceutical composition in a tablet dosage form comprising:
(a) about 20 mg to about 80 mg of a proton pump inhibitor selected from omeprazole and esomeprazole, or a pharmaceutically acceptable salt, solvate or polymorph thereof;
(b) about 400 mgs to about 1,400 mgs of directly compressible sodium bicarbonate;
(c) about 2 wt-% to about 8 wt-% of a disintegrant;
(d) about 3 wt-% to about 10 wt-% of a binder; and
(e) about 0.5 wt-% and about 3 wt-% of a lubricant.
43 . The pharmaceutical composition of claim 42 , wherein the tablet achieves an in vitro initial rise in pH within about 4 minutes.
44 . The pharmaceutical composition of claim 42 , wherein the tablet achieves an in vitro initial rise in pH to at least about 4 within about 4 minutes.
45 . The pharmaceutical composition of claim 42 , wherein upon administration to a fasted subject, the tablet provides a T max between about 30 minutes and about 45 minutes on Day 1.
46 . The pharmaceutical composition of claim 42 , wherein upon administration to a fasted subject, the tablet provides a T max of about 45 minutes on Day 7.
47 . The pharmaceutical composition of claim 42 , wherein the binder is hydroxypropyl cellulose and is present in an amount of about 3 wt-%.
48 . The pharmaceutical composition of claim 42 , wherein the disintegrant is croscarmellose sodium and is present in an amount of about 3 wt-%.
49 . The pharmaceutical composition of claim 42 , wherein the lubricant is sodium stearyl fumarate and is present in an amount of about 0.5 wt-% to about 5 wt-%.
50 . The pharmaceutical composition of claim 42 , wherein the directly compressible sodium bicarbonate is a combination of sodium bicarbonate and hydroxypropyl cellulose.
51 . The pharmaceutical composition of claim 42 , wherein the directly compressible sodium bicarbonate comprises between about 90-98 wt-% sodium bicarbonate and about 2-10 wt-% hydroxypropyl cellulose.
52 . The pharmaceutical composition of claim 42 , wherein the directly compressible sodium bicarbonate comprises about 97 wt-% sodium bicarbonate and about 3 wt-% hydroxypropyl cellulose.
53 . The pharmaceutical composition of claim 42 , wherein the directly compressible sodium bicarbonate comprises about 95 wt-% sodium bicarbonate and about 5 wt-% hydroxypropyl cellulose.
54 - 71 . (canceled)